Mice overexpressing latent TGF-beta1 are protected against renal fibrosis in obstructive kidney disease

Am J Physiol Renal Physiol. 2008 Jul;295(1):F118-27. doi: 10.1152/ajprenal.00021.2008. Epub 2008 Apr 30.


Transforming growth factor (TGF)-beta1, once activated, binds to its receptors and mediates renal fibrosis via the downstream Smad signaling pathway. We reported here that mice overexpressing latent TGF-beta1 in keratinocytes were protected against renal fibrosis in a model of obstructive kidney disease. In normal mice, both transgenic (Tg) and wild-type (WT) mice had normal renal histology and function, despite a 10-fold increase in plasma latent TGF-beta1 in Tg mice. A severe renal fibrosis was developed in WT mice at 7 days after urinary obstruction. Unexpectedly, renal fibrosis was prevented in Tg mice, although levels of latent TGF-beta1 in both circulation and renal tissues remained high. Compared with the WT mice, quantitative real-time PCR showed that upregulation of renal alpha-smooth muscle actin (SMA), collagen I, and collagen III mRNA was inhibited in Tg mice (60-70% reduced, all P < 0.01). These were further confirmed by immunohistochemistry with a marked inhibition of tubulointerstitial accumulation of alpha-SMA+ fibroblasts, collagen I, and collagen III matrix in Tg mice (all P < 0.001). Further studies showed that inhibition of renal fibrosis in Tg mice was associated with a significant reduction in renal TGF-beta1 and CTGF (60% reduced, P < 0.05), an increase in renal Smad7, a suppression of TSP-1 (a critical factor for TGF-beta1 activation), and an inhibition of Smad2/3 activation (all P < 0.001). In conclusion, latent TGF-beta may play a protective role in renal fibrosis. Inhibition of renal TGF-beta1 expression and activation, thereby blocking the downstream TGF-beta signaling pathway, may be a critical mechanism by which latent TGF-beta1 protects against renal fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / biosynthesis
  • Animals
  • Collagen Type I / biosynthesis
  • Collagen Type III / biosynthesis
  • Fibrosis
  • Immunohistochemistry
  • Kidney / pathology*
  • Kidney Diseases / pathology
  • Kidney Diseases / prevention & control*
  • Mice
  • Mice, Transgenic
  • Signal Transduction
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta1 / biosynthesis*
  • Up-Regulation


  • Actins
  • Collagen Type I
  • Collagen Type III
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1